tbuckley/cabot-search huggingface dataset:
Machine learning models for accurate pretreatment prediction of chemotherapy associated LV dysfunction in patients with breast cancer and lymphoma receiving chemotherapy (WF-98213 PREVENT and CCCWFU9912 DETECT IV).
Authors: Suditi Shyamsunder, Ralph D'Agostino, Nathaniel S. O'Connell, Amy Ladd, Kathryn E. Weaver, Glenn Jay Lesser, William Gregory Hundley, Mary Helen Hackney, Susan Anitra Melin, Yaorong Ge
Journal: Journal of Clinical Oncology (2022)

1553 Background: Cancer survivors receiving potentially cardiotoxic chemotherapy are at increased risk for developing left ventricular (LV) dysfunction. We implemented machine learning (ML) models to predict future LV dysfunction in patients with breast cancer or lymphoma scheduled to receive potentially cardiotoxic chemotherapy. Methods: We utilized prospectively collected data from NIH studies R01HL118740 (supported by the Wake Forest NCORP Research Base (UG1CA189824)) and R01CA167821. Data included measurements of LV function and demographic factors before, during, and 24 months after initiating potentially cardiotoxic chemotherapy. The two datasets were used both separately and collectively in the development of multiple ML models including penalized linear regression, support vector machine, and random forest (RF). A data preprocessing step properly handled missing information, data imbalance, and encoding. Hyperparameter tuning was performed using cross validation of training data. The final models were assessed with a 20% hold-out test dataset. Cardiotoxicity was defined as a pre- to 24-month post cancer treatment decline in LV ejection fraction (LVEF) of &gt; 10% or to an absolute value of &lt; 50%. Results: 276 patients were included in ML models (7% men, 93% women; age 52±13 years). The RF model based on the combined dataset had the best performance with a prediction accuracy, sensitivity, and specificity of 0.94, 0.81, and 0.98, respectively. The most important variables assessed pre-treatment as measured by the Gini impurity factor were in descending order, LVEF, global LV circumferential strain, LV end-systolic volume, body mass index, LV stroke volume, LV end-diastolic volume, and LV mass. Conclusions: Prior to cancer treatment, supervised ML methods such as RF models predicted declines in LVEF of &gt; 10% and/or to absolute values below 50% would occur 24 months after initiating chemotherapy for breast cancer or lymphoma. With further improvement and validation using larger datasets, these models may play an important role in cardio-oncology care during and following cancer treatment.
The Development of Global Cancer Research at the United States National Cancer Institute
Authors: Mark Parascandola, Paul C Pearlman, Linsey Eldridge, Satish Gopal
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract International research and collaboration has been a part of the National Cancer Institute’s (NCI) mission since its creation in 1937. Early on, efforts were limited to international exchange of information to ensure that US cancer patients could benefit from advances in other countries. As NCI’s research grant portfolio grew in the 1950s, it included a modest number of grants to foreign institutions, primarily in the United Kingdom and Europe. In the 1960s, the development of geographic pathology, which aimed to study cancer etiology through variations in cancer incidence and risk factors, led to an increase in NCI-funded international research, including research in low- and middle-income countries. In this paper, we review key international research programs, focusing particularly on the first 50 years of NCI history. The first NCI-led overseas research programs, established in the 1960s in Ghana and Uganda, generated influential research but also struggled with logistical challenges and political instability. The 1971 National Cancer Act was followed by the creation of a number of bilateral agreements with foreign governments, including China, Japan, and Russia, to support cooperation in technology and medicine. Although these agreements were broad without specific scientific goals, they provided an important mechanism for sustained collaborations in specific areas. With the creation of the NCI Center for Global Health in 2011, NCI’s global cancer research efforts gained sustained focus. Because the global cancer burden has evolved over time, increasingly impacting low- and middle-income countries, NCI’s role in global cancer research remains more important than ever.
Did We Forget That Masks, Lockdowns, and Other Nonpharmaceutical Interventions Also Play a Role in Respiratory Viral Disease?—Reply
Authors: William Encinosa, Jessica Figueroa, Youssef Elias
Journal: JAMA Pediatrics (2022)

Did We Forget That Masks, Lockdowns, and Other Nonpharmaceutical Interventions Also Play a Role in Respiratory Viral Disease?
The interaction between anti-PF4 antibodies and anticoagulants in vaccine-induced thrombotic thrombocytopenia
Authors: Anurag Singh, Filip Toma, Günalp Uzun, Teresa R. Wagner, Lisann Pelzl, Jan Zlamal, Verena Freytag, Karoline Weich, Stefanie Nowak-Harnau, Ulrich Rothbauer, Karina Althaus, Tamam Bakchoul
Journal: Blood (2022)
MEDB-07. Long-term medical and functional outcomes of medulloblastoma survivors: a population-based, matched cohort study
Authors: Hallie Coltin, Priscila Pequeno, Ning Liu, Derek S Tsang, Michael D Taylor, Eric Bouffet, Paul C Nathan, Vijay Ramaswamy
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Most medulloblastoma survivors suffer from late treatment-related sequelae. There are no population-based studies examining such late effects in a dedicated cohort of medulloblastoma survivors. METHODS: Using a provincial pediatric cancer registry, all 5+ year medulloblastoma survivors diagnosed between 1987-2015 in Ontario, Canada were identified and matched to cancer-free population controls based on age, sex, and geographical location. Cases were followed from the index date (five years from latest of diagnosis, or relapse or subsequent malignancy prior to age 18 years) until December 31, 2020 or censorship (death, or relapse or new cancer after age 18 years). Clinical data were linked to administrative health databases to estimate cumulative incidences and cause-specific hazard ratios (HR) of mortality, hospitalizations, strokes, hearing loss requiring a hearing aid, and receipt of homecare services between cohorts, accounting for matching and competing risks. RESULTS: We identified 230 cases [65.7% female; median diagnostic age: 7y, interquartile range (IQR) 4-10; median attained age: 24y, IQR 18-31] and 1150 controls. One hundred eighty-seven (81.3%) received craniospinal irradiation. Ten-year survival probability after index was 92.4% in cases and 99.4% in controls (HR 21.5, 95% CI 9.8-54.0). Cases were at higher risk for hospitalizations (HR 3.4, 95% CI 2.7-4.3), stroke (HR 45.6, 95% CI 12.8-289.8), hearing loss (HR 96.3, 95% CI 39.7-317.3), and requiring homecare services (HR 7.9, 95% CI 5.8-10.9). By 10 years after index, 4.8% (95% CI 2.2-9.0) of survivors had experienced a stroke compared to 0.1% (95% CI 0.01-0.7) of controls. CONCLUSIONS: Survivors of childhood medulloblastoma experienced an increased risk of mortality and serious morbidity compared to population controls. Consideration for mitigation strategies or early interventions in preventing neurovascular sequelae and hearing loss is warranted, as are dedicated supports for survivors.
HGG-08. Lorlatinib for the treatment of ALK fusion positive infant high grade glioma
Authors: Alyssa Greenwell, Deniz Altinok, Neena Marupudi, William Kupsky, Hamza Gorsi
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: High grade gliomas (HGG) are very rare in the infant age group with approximately 800 cases diagnosed in the USA and Europe each year. Histologically, HGG in infants resemble HGG in older children and adults but have distinct molecular features like ALK, NTRK, MET and ROS1 fusions. HGG in infants have superior outcomes compared to older age groups (5-year overall survival &amp;gt;50%) when treated with a radiation sparing regimen. Here we present the unique treatment course for an infant with ALK fusion positive HGG, including molecularly targeted therapy. CASE DESCRIPTION: A 3-month-old African-American female presented with acute onset vomiting, right facial droop and focal seizures. MRI of the brain revealed a right frontal intraparenchymal mass. Upfront gross total resection (GTR) was performed and histologic diagnosis of epithelioid glioblastoma was made. The molecular analysis of the tumor showed ZNF397-ALK fusion. The patient was treated with a radiation sparing regimen consisting of Carboplatin 8 mg/kg x 2 days and Etoposide 3 mg/kg x 3 days for 6 cycles. The patient tolerated the chemotherapy and had no evidence of disease recurrence at the completion of chemotherapy. However, 8 months after completion of therapy, she had a localized relapse and underwent a second GTR. Repeat molecular analysis confirmed the presence of ZNF 397-ALK fusion. She was started on Lorlatinib at 95 mg/m2/day once a day. She continued on the medication for 15 months and had no evidence of disease at the end of 15 months. During the course of her treatment, she had excessive weight gain (CTCAE grade-3) despite dose reduction. CONCLUSION: Infant high grade gliomas have a high prevalence of gene fusions including ALK fusions. This case shows that these fusions may be amenable to molecularly targeted treatments and should be studied in prospective clinical trials.
Contemporary management of renal transplant recipients with de novo urinary stones. A single institution experience
Authors: J.B. Ortiz Salvador, J. Bolón Marset, M. Ramos Cebrián, F. Gómez-Palomo, A. Bernal-Gomez, O. Colet, F. Quereda-Flores, A.J. Bevia Romero, D. Castillo-Anton, J. Espinosa-Vaño, P. Bahilo Mateu, D.G. Ordaz Jurado, J.D. López-Acón, M. Trassierra Villa, E. Broseta Rico, A. Budía Alba
Journal: European Urology (2022)
Quercetin ameliorates XIAP deficiency–associated hyperinflammation
Authors: Samuel C. C. Chiang, Erika Owsley, Neelam Panchal, Vijaya Chaturvedi, Catherine E. Terrell, Michael B. Jordan, Parinda A. Mehta, Stella M. Davies, Nagako Akeno, Claire Booth, Rebecca A. Marsh
Journal: Blood (2022)
OTHR-04. Single-nucleus transcriptomic atlas of human hindbrain development identifies cellular origins of pediatric brainstem tumors
Authors: Piyush Joshi, Konstantin Okonechnikov, Mari Sepp, Ioannis Sarropoulos, Kevin Leiss, Lena M Kutscher, Henrik Kaessmann, Stefan M Pfister
Journal: Neuro-Oncology (2022)

Abstract The hindbrain is a key central nervous system structure involved in communication between the brain and the spinal cord, integrating sensory information and coordinating motor responses. Dysregulation in hindbrain development is frequently associated with behavioral disorders and maybe associated tumor formation, stressing the importance of understanding the intricacies of human hindbrain development. Here we performed RNA-sequencing of over 300,000 single nuclei to construct a developing human hindbrain atlas, focusing on pons and medulla, ranging from embryonic to adult stages, profiling the entirety of the hindbrain’s neural and glial populations from progenitors to mature cell types. We describe the transcriptional identity of neuronal cells constituting the pontine and medullary nerve centers including precerebellar, respiratory, auditory and vestibular nuclei; and their differentiation trajectory from the progenitor domains in the embryonic rhombencephalon. To identify the origins of pediatric brain tumors, we mapped ~2,900 bulk and ~50 single-cell transcriptome tumor datasets to the developmental hindbrain atlas, focusing on medulloblastomas, and pediatric low- and high-grade gliomas, and determined cell populations and differentiation states associated with specific tumor groups. We confirmed migrating lower rhombic lip derivatives as the lineage of origin for WNT medulloblastoma. Further, we ascertained early ventral neural progenitor-derived oligodendrocyte lineage as the source of diffuse midline glioma H3K27-altered and postnatal oligodendrocyte progenitors as the origin of pilocytic astrocytoma. In addition, the ependymal lineage originating from glial progenitors was identified as the best match for ependymomas. We show that tumor development has a component that transcriptomically follows its cellular lineage of origin, and identify genes with preserved expression between the respective normal and malignant cell populations. Tumor to normal comparisons also identified tumor-specific genes, providing promising therapeutic candidates. We plan to make our data and analysis pipeline publicly available via user-friendly graphical interface at brain-match.org for unrestricted use of the generated results.
Ultra-low-dose CT versus chest X-ray for patients suspected of pulmonary disease at the emergency department: a multicentre randomised clinical trial
Authors: Inge A H van den Berk, Maadrika M N P Kanglie, Tjitske S R van Engelen, Josje Altenburg, Jouke T Annema, Ludo F M Beenen, Bart Boerrigter, Marije K Bomers, Paul Bresser, Elvin Eryigit, Maarten Groenink, Suzanne M R Hochheimer, Frits Holleman, Jos A J Kooter, Ramon B van Loon, Mitran Keijzers, Ivo van der Lee, Paul Luijendijk, Lilian J Meijboom, Saskia Middeldorp, Laura J Schijf, Robin Soetekouw, Ralf W Sprengers, Alexander D Montauban van Swijndregt, Wouter de Monyé, Milan L Ridderikhof, Michiel M Winter, Shandra Bipat, Marcel G W Dijkgraaf, Patrick M M Bossuyt, Jan M Prins, Jaap Stoker
Journal: Thorax (2022)

Background Chest CT displays chest pathology better than chest X-ray (CXR). We evaluated the effects on health outcomes of replacing CXR by ultra-low-dose chest-CT (ULDCT) in the diagnostic work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. Methods Pragmatic, multicentre, non-inferiority randomised clinical trial in patients suspected of non-traumatic pulmonary disease at the emergency department. Between 31 January 2017 and 31 May 2018, every month, participating centres were randomly allocated to using ULDCT or CXR. Primary outcome was functional health at 28 days, measured by the Short Form (SF)-12 physical component summary scale score (PCS score), non-inferiority margin was set at 1 point. Secondary outcomes included hospital admission, hospital length of stay (LOS) and patients in follow-up because of incidental findings. Results 2418 consecutive patients (ULDCT: 1208 and CXR: 1210) were included. Mean SF-12 PCS score at 28 days was 37.0 for ULDCT and 35.9 for CXR (difference 1.1; 95% lower CI: 0.003). After ULDCT, 638/1208 (52.7%) patients were admitted (median LOS of 4.8 days; IQR 2.1–8.8) compared with 659/1210 (54.5%) patients after CXR (median LOS 4.6 days; IQR 2.1–8.8). More ULDCT patients were in follow-up because of incidental findings: 26 (2.2%) versus 4 (0.3%). Conclusions Short-term functional health was comparable between ULDCT and CXR, as were hospital admissions and LOS, but more incidental findings were found in the ULDCT group. Our trial does not support routine use of ULDCT in the work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. Trial registration number NTR6163.
Evolution of biomarker testing in advanced non-small cell lung cancer (aNSCLC) and metastatic breast cancer (mBC) in U.S. community practices.
Authors: Lee S. Schwartzberg, Elaine Yu, Craig S. Meyer, Anuj Shah, Richard Price, Tania Szado, Daniel A. Vaena, Davey B. Daniel, Dennis Slater, Harry Staszewski, Bruno Fang, Lasika Seneviratne, Esprit Ma
Journal: Journal of Clinical Oncology (2022)

e18778 Background: Biomarker testing has advanced from single-gene to NGS. This study examined aNSCLC and mBC biomarker testing ≤ 90d of advanced (adv) or metastatic (met) diagnosis (Dx) and treatment (tx) patterns at US practices. Methods: A retrospective observational study used Flatiron Health electronic health-record-derived de-identified database at OneOncology (OO) community and non-OO Flatiron Health nationwide (NAT) sites (̃90% community, ̃10% academic). Patients (Pts) ≥ 18y, with Dx of aNSCLC or mBC from 1/1/18 - 4/30/21, with ≥ 1 visit ≤ 90d after adv/met Dx and ≥ 90d follow-up were evaluated. Descriptive analyses and logistic regression were used. Results: A total of 16,882 pts with aNSCLC (2366 OO; 14,516 NAT), and 6500 pts with mBC (1026 OO; 5474 NAT) were included. Overall testing was high and stable (OO: 85% aNSCLC, 98% mBC; NAT: 84%, 97%) with higher NGS testing at OO (58% aNSCLC; 28% mBC) vs NAT (49%; 16%) (Table), which reflected more pts with aNSCLC tested for all 6 mutations (ALK, BRAF, KRAS, ROS-1, EGFR, PD-L1; 54% OO vs 50% NAT, p&lt;0.001) and more pts with mBC tested for PIK3CA (27% OO vs 16% NAT, p&lt;0.001). In aNSCLC, NGS testing increased similarly for OO and NAT over time (p&gt;0.05); mBC NGS testing increased faster at NAT vs OO (p&lt;0.05). Of pts tested and treated, 16% aNSCLC (1945 OO; 11,376 NAT) and &lt; 3% mBC (14 OO; 108 NAT) received tx before test results were available. For pts with aNSCLC with ≥ 1 actionable mutation (ALK, BRAF, ROS-1, EGFR), 18% OO and 22% NAT had tx before test results. Cancer immunotherapy plus chemotherapy was the most common tx (36 % OO vs 40 % NAT); after test results, 33% vs 56% OO and 45% vs 44% NAT pts stayed on tx vs switched to targeted tx. For pts with aNSCLC with ≥ 1 aforementioned actionable mutations who waited until test results were available, 65% received targeted tx at OO and NAT. Conclusions: Biomarker testing has become standard of care in aNSCLC and mBC in US community settings. NGS rates increased over time and were higher at OO vs NAT. Differences in pts treated before test results reflects the need to wait for NGS results to inform initial tx in aNSCLC vs non-NGS results for mBC. This study shows NGS testing in US community practices has increased since 2018, particularly in mBC, but opportunities remain to optimize NGS results into tx decisions.[Table: see text]
Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases
Authors: Kareem Khalaf, Paolo Tornese, Antoniangela Cocco, Alberto Albanese
Journal: Translational Neurodegeneration (2022)

Abstract Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. In recent years, hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases. Experimental evidence on the mechanisms underlying TUDCA’s neuroprotective action derives from animal models of Alzheimer’s disease, Parkinson’s disease, Huntington’s diseases, amyotrophic lateral sclerosis (ALS) and cerebral ischemia. Preclinical studies indicate that TUDCA exerts its effects not only by regulating and inhibiting the apoptotic cascade, but also by reducing oxidative stress, protecting the mitochondria, producing an anti-neuroinflammatory action, and acting as a chemical chaperone to maintain the stability and correct folding of proteins. Furthermore, data from phase II clinical trials have shown TUDCA to be safe and a potential disease-modifier in ALS. ALS is the first neurodegenerative disease being treated with hydrophilic bile acids. While further clinical evidence is being accumulated for the other diseases, TUDCA stands as a promising treatment for neurodegenerative diseases.
MEDB-05. Survival and prognostic factors in childhood medulloblastoma: A China single center experience from 2006 to 2015
Authors: zhuangzhuang Liang, liangliang Cao, yang Zhao, baocheng Wang, shuaiwei Tian, jiajia Wang, jie Ma
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE: Medulloblastoma (MB) is a malignant embryonal tumor that develops especially in childhood, with overall survival (OS) at 5 years of up to 70%. The aim of the study is to explore the clinical profile and outcome among the histo-molecular subgroups in Chinese children. METHODS: A total of 93 patients of MB who underwent surgical treatment at Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2006 to December 2015. The clinical profile, treatment, and survival patterns are discussed. The relevant statistical analysis was done using SPSS software, version 21.0. RESULTS: At the most recent follow-up date, 15 (16.1%) had been lost to follow-up，78 cases were tested for RNA-seq, of which 54 cases were successful, and 24 cases failed the quality control due to sample quality problems.The male-to-female ratio was 2.4:1, and the patients’ mean age at diagnosis was 5 years (ranged from 4 months to 11 years).The estimated 5-year overall survival and progression-free survival, based on Kaplan-Meier analysis, were 55.1% ± 5.6% and 40.9% ± 5.7%.Multivariate survival analysis showed that progression -free survival were significantly affected by extent of surgery (P=0.026) and postoperative radiotherapy(P＜0.001).Preoperative metastasis (P=0.032) and postoperative radiotherapy (P=0.001) had a significant influence on overall survival. While，the molecular subtypes showed no statistically significant differences in 5-year PFS and 5-year OS. CONCLUSION: Extent of resection of MB and postoperative radiotherapy were the important clinical prognostic factors for survival. In the future, we will continue to expand cases and study the clinical characteristics and prognostic risk factors of different molecular types of medulloblastoma in Chinese children,and to improve the survival rate of children with medulloblastoma.